Inhalable imatinib metabolite formulations, manufacture, and uses thereof

ABSTRACT

The invention relates to inhalable imatinib metabolite formulations, manufacture, and uses thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application claims the benefit of, and priority to, U.S.Provisional Application Nos. 62/849,054, filed May 16, 2019; 62/849,056,filed May 16, 2019; 62/849,058, filed May 16, 2019; 62/849,059, filedMay 16, 2019; 62/877,575, filed Jul. 23, 2019; 62/942,408, filed Dec. 2,2019; 62/984,037, filed Mar. 2, 2020; and 62/958,481, filed Jan. 8,2020; the content of each of which is hereby incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The invention relates to inhalable imatinib metabolite formulations,manufacture, and uses thereof.

BACKGROUND

Pulmonary arterial hypertension (PAH) is a condition involving elevatedblood pressure in the arteries of the lungs with unknown causes and isdifferentiated from systemic hypertension. PAH is a progressive diseasewhere resistance to blood flow increases in the lungs causing damage tothe lungs, the pulmonary vasculature and the heart that can eventuallylead to death. While symptoms are treatable with vasodilators and othermedications, there is no known disease modifying therapy or cure andadvanced cases can eventually require lung transplants.

Imatinib, especially the mesylate salt thereof, is a tyrosine kinaseinhibitor approved for use in treating certain types of cancer.Imatinib's potential to inhibit the tyrosine kinase PDGFR(platelet-derived growth factor receptor) which is highly upregulated inthe pulmonary arteries in cases of PAH, led to interest in its use intreating PAH. See, Olschewski, H, 2015, Imatinib for Pulmonary ArterialHypertension—Wonder Drug or Killer Drug? Respiration, 89:513-514,incorporated herein by reference. To that end, studies have beenconducted to determine the potential of imatinib in treating PAH andpatients have been found to respond favorably to said treatment.Unfortunately, an unacceptable amount of severe adverse events includingsubdural hematoma blunted enthusiasm for the drug. Frost, et al., 2015,Long-term safety and efficacy of imatinib in pulmonary arterialhypertension, J Heart Lung Transplant, 34(11):1366-75, incorporatedherein by reference.

SUMMARY

Compositions and methods of the invention address problems withimatinib-based PAH treatments through the use of specializedformulations and delivery mechanisms. Particularly, the inventionrecognizes that direct delivery to the lung tissues through inhalationcan offer greater lung exposure than equivalent doses of imatinib orsalts thereof administered through conventional oral routes or by IV.Accordingly, while a relatively high oral dose of imatinib or imatinibmesylate would be required to achieve the same target lung exposure asachieved by inhalation of the inventive formulations. Therefore, the useof inhalable formulations of the invention allows for therapeuticamounts of imatinib, its active metabolite, or salts thereof to reachthe lungs for treatment of PAH and other conditions of the pulmonarycardiovascular system without the adverse events experienced withprolonged oral administration of imatinib mesylate.

The primary active metabolite of imatinib is N-desmethyl imatinib andhas been found to exhibit the same potency as the imatinib parentcompound. Additionally, N-desmethyl imatinib exhibits an increasedhalf-life relative to the parent imatinib compound. Compounds andmethods of the invention take advantage of this characteristic byproviding inhalable formulations of N-desmethyl imatinib in the absenceof the parent compound. Such formulations provide therapeutic benefitsin treating PAH and other conditions with more efficient delivery to andlonger residence in the effected tissue due to the increased half-lifeof the metabolite. This combination can allow for fewer doses with lowerconcentrations of active pharmaceutical ingredient relative toconventional oral or IV administration of imatinib mesylate.

In certain embodiments inhalable N-desmethyl imatinib formulations maybe micronized through wet or dry milling (e.g., jet milling) to achievethe desired particle size for dry powder formulations for inhalation.N-desmethyl imatinib or appropriate salts thereof may be micronized toparticle sizes of about 0.5 μm to about 5 μm mass median aerodynamicdiameter (MMAD) for desired deep lung penetration. Inhaled products canbe limited in terms of mass of powder that can be administered andcertain imatinib salts will contribute significantly to the molecularweight of the inhaled compound. Accordingly, in certain embodiments, theimatinib metabolite may be preferred for efficient delivery of theactive moiety to lung tissue. If required, various excipients orcarriers can be added the metabolite or salts thereof before or aftermicronization depending on application. For example, carriers,excipients, conditioners, and force control agents may be included withlactose (which may be conditioned with various solvents to increaseseparation of imatinib during inhalation), magnesium stearate, leucine,isoleucine, dileucine, trileucine, lecithin,distearylphosphatidylcholine (DSPC) or other lipid-based carriers, orvarious hydrophilic polymers. The skilled artisan will appreciate thatexcipients or carriers are optional and that many embodiments of theinvention do not require excipients or carriers.

Because the inhalable formulations described herein can modulate theuptake of imatinib in the target tissue of the lungs ormicrovasculature, formulations of the invention can be used to treatvarious conditions of the pulmonary cardiovascular system while avoidingthe adverse events associated with higher doses that are administered byother routes of administration that introduce the drug systemicallyprior to reaching the target tissue. For example, compounds and methodsof the invention can be used to treat PAH as well as lung transplantrejection, pulmonary veno-occlusive disease (PVOD) and pulmonaryhypertension secondary to other diseases like heart failure withpreserved ejection fraction (HFpEF) or schistosomiasis. Dose ranges caninclude between about 10 mg to about 100 mg per dose for inhalation on atwice to four times per day schedule. About 0.1 mg to about 20 mg ofN-desmethyl imatinib may then be present within the lungs afterinhalation.

Methods and formulations of the invention may include spray-driedN-desmethyl imatinib or salts thereof for inhalation. While carrierssuch as lactose may be used after micronization to aid in delivery viainhalation, those carriers may generally comprise larger diameterparticles and complication in the separation of the active imatinibmetabolite may result in lower amounts of the inhaled compound reachingthe lungs. Furthermore, the amount of active compound reaching the lungsmay be less predictable using such carriers and methods, making dosingmore complicated. Accordingly, spray-dried methods may be used whereinN-desmethyl imatinib or salts thereof along with various excipients orother additives may be micronized to a desired particle size andsuspended or solubilized for spray-drying and inhalation.

In certain embodiments, the micronized imatinib metabolite is suspendedin a feedstock for the purposes of spray-drying to avoid the creation ofamorphous or polymorphic N-desmethyl imatinib content that may occur ifdissolved in a solution (e.g. in an appropriate organic solvent orwithin an acidified aqueous solution) upon spray-drying. By creating astable suspension of micronized N-desmethyl imatinib for spray-drying,once dried, the inhalable formulation can retain the desired crystalstructure, particle size, and low levels of amorphous content obtainedbefore the micronization process.

Stable suspensions for spray-drying may be obtained through manipulationof factors affecting compound solubility such as pH, ionic strength, anddispersing agents or surfactants. Excipients that may be used beforemicronization in the spray-drying methods described above include, forexample, leucine, dileucine, trileucine, bulking agents such astrehalose or mannitol, lecithin, DSPC or other lipid-based carriers,citrate, or acetate.

The inhalable formulation may be in a dry powder. In some embodiments,the inhalable formulation may be a suspension of crystalline N-desmethylimatinib. The N-desmethyl imatinib may be present in a therapeuticallyeffective amount to treat a condition of the pulmonary cardiovascularsystem, such as pulmonary arterial hypertension (PAH). The salt may beat least one selected from the group consisting of glycollate,isethionate, xinafoate, furoate, trifenatate, HCl, sulfate, phosphate,lactate, maleate, malate, fumarate, tartrate, succinate, adipate,citrate, and malonate. The inhalable formulation may further include oneor more carrier agents.

Aspects of the invention include an inhalable formulation comprisingN-desmethyl imatinib or a salt thereof, wherein the formulation does notinclude imatinib. The N-desmethyl imatinib may be present in atherapeutically effective amount to treat a condition of the pulmonarycardiovascular system which may be pulmonary arterial hypertension(PAH). The inhalable formulation can be a dry powder and can includemicronized particles comprising a mass median aerodynamic diameter inthe range of 0.5-5 μm.

In salt formulations, the salt may be selected from mesylate,glycollate, isethionate, xinafoate, furoate, trifenatate, HCl, sulfate,phosphate, lactate, maleate, malate, fumarate. In certain embodiments,the inhalable formulation can include one or more carrier agents. Thecarrier agent can be selected from lactose, magnesium stearate, leucine,isoleucine, dileucine, trileucine, lecithin, anddistearylphosphatidylcholine (DSPC).

In certain aspects, the invention can include methods of treating acondition of the pulmonary cardiovascular system by providing to asubject an inhalable formulation comprising N-desmethyl imatinib or asalt thereof, wherein the formulation does not include imatinib. Invarious embodiments, the subject may be a human and the condition of thepulmonary cardiovascular system can be pulmonary arterial hypertension(PAH).

DETAILED DESCRIPTION

The invention relates to inhalable formulations of N-desmethyl imatiniband salts thereof. N-desmethyl imatinib is the primary active metaboliteof imatinib formed when imatinib undergoes demethylation by thecytochrome P450 (CYP) isomer CYP3A4. N-desmethyl imatinib has thefollowing structure:

The methods and compositions described herein provide greaterconcentrations of N-desmethyl imatinib in target lung tissue thanobtained with equivalent doses administered orally or through IV.Furthermore, N-desmethyl imatinib has been found to exhibit the samepotency as the imatinib parent compound but exhibits an increasedhalf-life relative to the parent imatinib compound. Accordingly,inhalable formulations of N-desmethyl imatinib as described hereinprovide therapeutic benefits with reduced risk of adverse events throughmore efficient delivery to and longer residence in the effected tissuerelative to conventional oral or IV administration of imatinib mesylate.

Thus, the invention provides improved treatment methods for lifethreatening disease that were heretofore too risky for practicalapplication.

In certain embodiments, compounds of the invention include formulationsof N-desmethyl imatinib or salts thereof. In preferred embodiments,N-desmethyl imatinib is used in a formulation (either in dry powder orsuspension) for inhalation to treat a condition of the pulmonarycardiovascular system such as PAH. Certain salt forms are alsocontemplated. In various embodiments, salts contemplated herein includeglycollate, isethionate, malonate, tartrate, and malate. Other saltforms contemplated herein are xinafoate, furoate, trifenatate, HCl,sulfate, phosphate, lactate, maleate, fumarate, succinate, adipate, andcitrate

In various embodiments, micronized N-desmethyl imatinib and saltsthereof retain crystallinity, even after micronization and spray drying(as discussed in detail below). Of particular note is, by suspendingmicronized N-desmethyl imatinib particles in a solution as opposed tosolubilizing, the desired crystalline form and low amorphous contentobtained during micronization is carried through to the spray-driedinhalable powder because the N-desmethyl imatinib crystals are notdissolved in the solution to a significant degree.

In various embodiments, N-desmethyl imatinib or salts thereof areprovided in dry powder formulations for inhalation. Dry powder can beadministered via, for example, dry powder inhalers such as described inBerkenfeld, et al., 2015, Devices for Dry Powder Drug Delivery to theLung, AAPS PharmaSciTech, 16(3):479-490, incorporated herein byreference. Dry powder compounds may be divided into single doses forsingle, twice daily, three times daily, or four times daily inhalationto treat disorders such as PAH or other conditions of the pulmonarycardiovascular system. The single doses may be divided into individualcapsules or other formats compatible with the dry powder inhaler to beused.

In other embodiments, N-desmethyl imatinib suspensions having thecharacteristics described herein (e.g., low polymorphism and amorphouscontent) can be delivered via inhalation using, for example, anebulizer. N-desmethyl imatinib suspensions may offer advantages oversolutions as discussed below. For nebulized suspensions, micronizationand particle diameter may be of particular importance for efficientdelivery and N-desmethyl imatinib may be preferably micronized to a massmedian diameter of 2 μm or less. The suspension solution for nebulizerinhalation can be aqueous and doses may be divided into individualcontainers or compartments for sterile storage prior to use.

Micronized N-desmethyl imatinib particle size can range from about 0.5μm to about 5 μm depending on application (e.g., dry powder orsuspension for inhalation). In preferred embodiments the size range isabout 1 μm to about 3 μm in dry powder formulations to achieve deep lungpenetration.

In certain embodiments, N-desmethyl imatinib formulations of theinvention may include one or more excipients. Excipients may include,for example, lactose in various forms (e.g., roller dried or spraydried). Larger lactose particles can be used as a carrier for inhalationof micronized N-desmethyl imatinib formulations. The carrier particles,with their larger size, can be used to increase aerodynamic forces onthe combined N-desmethyl imatinib/carrier in order to aid in deliverythrough inhalation. Solvents may be used to condition the lactosesurface such that the active component can be effectively separated fromthe lactose as it leaves the inhaler device and within the oral cavitywhen being used as a carrier. Magnesium stearate can be used as aforce-control agent or conditioning agent in various embodiments. Insome embodiments, leucine can be used as a force-control agent includingdifferent forms of leucine (e.g. isoleucine) along with dileucine andeven trileucine.

Lecithin phospholipids such as DSPC may be used as an excipient for drypowder inhalation. In certain embodiments, excipients may includevarious hydrophilic polymers. See, for example, Karolewicz, B., 2016, Areview of polymers as multifunctional excipients in drug dosage formtechnology, Saudi Pharm J., 24(5):525-536, incorporated herein byreference.

In various embodiments, the N-desmethyl imatinib formulations of theinvention may be pharmaceutical compositions for use in treating variousconditions of the pulmonary cardiovascular system, such as PAH. Forexample, N-desmethyl imatinib is a potent inhibitor of theplatelet-derived growth factor receptor (PDGFR). Accordingly, thecompositions of the invention may be used to treat any disease ordisorder that involves inhibition of PDGFR or other kinases sensitive toN-desmethyl imatinib.

In certain embodiments, the compositions of the invention may be used totreat PAH. For treatment of PAH or other disorders, a therapeuticallyeffective amount of a pharmaceutical composition of N-desmethyl imatinibaccording to the various embodiments described herein can be delivered,via inhalation (e.g., via dry powder inhaler or nebulizer) to deliverthe desired amount of N-desmethyl imatinib compound to the target lungtissue.

Dosages for treating PAH and other conditions of the pulmonarycardiovascular system may be in the range of between about 10 mg toabout 100 mg per dose for inhalation on once, twice or three times perday schedule. About 0.1 mg to about 20 mg of the active N-desmethylimatinib compound may then be present at the lung after inhalation. Incertain embodiments about 10 mg to 30 mg of N-desmethyl imatinib may begiven in a capsule for a single dry-powder inhalation dose with about 5mg to about 10 mg of the compound to be expected to reach the lungs. Ininhalable suspension embodiments, N-desmethyl imatinib may be present atabout 0.3 to about 1 mg/kg in a dose and may be administered one to fourtimes a day to obtain the desired therapeutic results.

In certain embodiments, N-desmethyl imatinib formulations of theinvention may be used to treat pulmonary hypertension as a result ofschistosomiasis. See, for example, Li, et al., 2019, The ABL kinaseinhibitor imatinib causes phenotypic changes and lethality in adultSchistosoma japonicum, Parasitol Res., 118(3):881-890; Graham, et al.,2010, Schistosomiasis-associated pulmonary hypertension: pulmonaryvascular disease: the global perspective, Chest, 137(6 Suppl):20S-29S,the content of each of which is incorporated herein by reference.

N-desmethyl imatinib pharmaceutical compositions of the invention may beused to treat lung transplant recipients to prevent organ rejection.See, Keil, et al., 2019, Synergism of imatinib, vatalanib and everolimusin the prevention of chronic lung allograft rejection after lungtransplantation (LTx) in rats, Histol Histopathol, 1:18088, incorporatedherein by reference.

In certain embodiments, pharmaceutical compositions described herein canbe used to treat pulmonary veno-occlusive disease (PVOD). See Sato, etal., 2019, Beneficial Effects of Imatinib in a Patient with SuspectedPulmonary Veno-Occlusive Disease, Tohoku J Exp Med. 2019 February;247(2):69-73, incorporated herein by reference.

For treatment of any conditions of the pulmonary cardiovascular systemfor which N-desmethyl imatinib may produce a therapeutic effect,compounds and methods of the invention may be used to provide greaterconcentration at the target lung tissue through inhalation along withconsistent, predictable pharmacokinetics afforded by low polymorphismand amorphous content. The efficient localization of therapeuticcompound at the target tissue allows for lower systemic exposure andavoidance of the adverse events associated with prolonged oraladministration of imatinib mesylate.

Methods of the invention can include preparation of N-desmethyl imatinibformulations. As noted above, N-desmethyl imatinib or salts thereof maybe administered via inhalation in suspension or dry powder form. Drypowder formulations may be obtained via any known method including, inpreferred embodiments, jet milling. Jet milling can be used to grindN-desmethyl imatinib and, potentially, various additives (e.g.,excipients) using a jet (or jets) of compressed air or gas to forcecollisions between the particles as they transit at near sonic velocityaround the perimeter of a toroidal chamber. The size reduction is theresult of the high-velocity collisions between particles of the processmaterial. Outputs of the jet mill may allow particles to exit theapparatus once a desired size has been reached. As noted herein, desiredparticle size for dry powder inhalation and other formulations may be inthe range of about 0.5 μm to about 5 μm.

In certain embodiments, bulk N-desmethyl imatinib may be micronized tothe desired size for inhalation via wet milling wherein the imatinibparticles are suspended in a slurry and reduced through shearing orimpact with a grinding media.

Once micronized, in dry powder form, N-desmethyl imatinib formulationsof the invention, with their low polymorphic and amorphous content, canbe prepared for inhalation. In certain embodiments, the dry powderN-desmethyl imatinib can be combined with larger carrier particles suchas lactose as discussed above.

In some embodiments an N-desmethyl imatinib suspension can be formed.The suspension may result from dry micronization followed by suspensionof the resulting dry powder or can be obtained as the outcome of a wetmilling procedure. N-desmethyl imatinib suspensions of micronizedcrystal forms may be used in nebulized inhalation treatment or may bespray dried for dry powder treatments.

Spray drying techniques are well characterized and described, forexample, in Ziaee, et al., 2019, Spray drying of pharmaceuticals andbiopharmaceuticals: Critical parameters and experimental processoptimization approaches, Eur. J. Pharm. Sci., 127:300-318, and Weers etal., 2019, AAPS Pharm Sci Tech. 2019 Feb. 7; 20(3):103. doi:10.1208/s12249-018-1280-0, and 2018/0303753, each of which isincorporated herein by reference. Spray drying micronized N-desmethylimatinib or salts thereof provides for uniform and predictablecrystallinity and particle size and can avoid the need for large carriermolecules that may adversely affect the amount of inhaled drug thatreaches the target lung tissue.

In spray-dried embodiments, micronized drug particles may be suspendedwithin a non-aqueous solvent or within an emulsion of a non-aqueoussolvent which, in turn is emulsified or dispersed within an aqueousenvironment (e.g. oil in water) and spray-dried, resulting incrystalline drug particles. The non-aqueous component may or may not befugitive and thus could be removed completely during spray drying or, itcould be retained, depending on the desired properties required. In suchembodiments, each atomized droplet (mass median diameter ˜10 μm)contains dispersed drug crystals. During the initial moments of thedrying process, the more volatile aqueous phase begins to evaporate. Therapidly receding atomized droplet interface drives enrichment of theslowly diffusing drug and emulsion particles at the interface. Thisleads to formation of a void space in the center of the drying droplet.As the drying process continues, the less volatile oil phase in theemulsion droplets evaporates, resulting in formation of hollow pores intheir place. Overall, the resulting hollow spray-dried compositeparticles contain drug crystals.

Maintaining a stable solution of crystalline N-desmethyl imatinib isimportant in certain embodiments of the formulations and methods of theinvention. Accordingly, formulation methods include manipulation of thesuspension to prevent dissolution of the N-desmethyl imatinib. Aqueoussolution factors such as pH, ionic strength and dispersing agents may beused to obtain a stable suspension for nebulized inhalation or spraydrying. For example, the pH of the aqueous solution may be adjusted toprevent dissolution. Solubility of the N-desmethyl imatinib increases asthe pH drops and, therefore, the pH of the aqueous solution in variousembodiments may be above and, preferably, the solution may be neutral.

Additionally, the presence of ions in aqueous solution may tend to ‘saltout’ the N-desmethyl imatinib. The solubility of the both N-desmethylimatinib and its mesylate salt may decrease with salinity. Accordingly,salt in the aqueous solution may be used to reduce solubility of theN-desmethyl imatinib crystals in certain embodiments.

To promote dispersion and thoroughly deagglomerate the N-desmethylimatinib particles, a dispersing agent or surfactant (e.g., Tween 20 orTween 80) may be added but should not cause dissolution of theN-desmethyl imatinib in suspension.

In certain embodiments, excipients can be added to the suspension beforespray drying. In various embodiments, the excipient may be awater-soluble excipient, such as leucine, dileucine, trileucine,trehalose, mannitol, citrate or acetate. In other embodiment, theexcipient may be a water insoluble excipient, such as lecithin,distearylphosphatidylcholine (DSPC) or limonene. Such insolubleexcipients may be dissolved in a non-aqueous medium that is miscible orimmiscible with water, thereby creating an emulsion. Alternatively, aliposomal dispersion could be created into which the suspendedN-desmethyl imatinib could be added and homogenized or where it could bespray dried in separate feedstocks.

When the compounds of the present invention are administered aspharmaceuticals, to humans and mammals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99.5% (morepreferably, 0.5 to 90%) of active ingredient, i.e., at least one atherapeutic compound of the invention and/or derivative thereof, incombination with a pharmaceutically acceptable carrier.

The effective dosage of each agent can readily be determined by theskilled person, having regard to typical factors each as the age,weight, sex and clinical history of the patient. In general, a suitabledaily dose of a compound of the invention will be that amount of thecompound which is the lowest dose effective to produce a therapeuticeffect. Such an effective dose will generally depend upon the factorsdescribed above.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

The pharmaceutical compositions of the invention include a“therapeutically effective amount” or a “prophylactically effectiveamount” of one or more of the compounds of the present invention, orfunctional derivatives thereof. An “effective amount” is the amount asdefined herein in the definition section and refers to an amounteffective, at dosages and for periods of time necessary, to achieve thedesired therapeutic result, e.g., a diminishment or prevention ofeffects associated with PAH. A therapeutically effective amount of acompound of the present invention or functional derivatives thereof mayvary according to factors such as the disease state, age, sex, andweight of the subject, and the ability of the therapeutic compound toelicit a desired response in the subject. A therapeutically effectiveamount is also one in which any toxic or detrimental effects of thetherapeutic agent are outweighed by the therapeutically beneficialeffects.

A “prophylactically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredprophylactic result. Typically, since a prophylactic dose is used insubjects prior to, or at an earlier stage of disease, theprophylactically effective amount may be less than the therapeuticallyeffective amount. A prophylactically or therapeutically effective amountis also one in which any toxic or detrimental effects of the compoundare outweighed by the beneficial effects.

Dosage regimens may be adjusted to provide the optimum desired response(e.g. a therapeutic or prophylactic response). For example, a singleinhalable bolus may be administered, several divided doses may beadministered over time or the dose may be proportionally reduced orincreased as indicated by the exigency of the therapeutic situation.Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular subject, composition, and mode ofadministration, without being toxic to the patient.

The term “dosage unit” as used herein refers to physically discreteunits suited as unitary dosages for the mammalian subjects to betreated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on (a) the unique characteristics of the compound, and (b) thelimitations inherent in the art of compounding such an active compoundfor the treatment of sensitivity in individuals.

In some embodiments, therapeutically effective amount can be estimatedinitially either in cell culture assays or in animal models, usuallymice, rabbits, dogs, or pigs. The animal model is also used to achieve adesirable concentration range and route of administration. Suchinformation can then be used to determine useful doses and routes foradministration in other subjects. Generally, the therapeuticallyeffective amount is sufficient to reduce PAH symptoms in a subject. Insome embodiments, the therapeutically effective amount is sufficient toeliminate PAH symptoms in a subject.

Dosages for a particular patient can be determined by one of ordinaryskill in the art using conventional considerations, (e.g. by means of anappropriate, conventional pharmacological protocol). A physician may,for example, prescribe a relatively low dose at first, subsequentlyincreasing the dose until an appropriate response is obtained. The doseadministered to a patient is sufficient to effect a beneficialtherapeutic response in the patient over time, or, e.g., to reducesymptoms, or other appropriate activity, depending on the application.The dose is determined by the efficacy of the particular formulation,and the activity, stability, or half-life of the compounds of theinvention or functional derivatives thereof, and the condition of thepatient, as well as the body weight or surface area of the patient to betreated. The size of the dose is also determined by the existence,nature, and extent of any adverse side-effects that accompany theadministration of a particular vector, formulation, or the like in aparticular subject. Therapeutic compositions comprising one or morecompounds of the invention or functional derivatives thereof areoptionally tested in one or more appropriate in vitro and/or in vivoanimal models of disease, such as models of PAH, to confirm efficacy,tissue metabolism, and to estimate dosages, according to methods wellknown in the art. In particular, dosages can be initially determined byactivity, stability or other suitable measures of treatment vs.non-treatment (e.g., comparison of treated vs. untreated cells or animalmodels), in a relevant assay. Formulations are administered at a ratedetermined by the LD50 of the relevant formulation, and/or observationof any side-effects of compounds of the invention or functionalderivatives thereof at various concentrations, e.g., as applied to themass and overall health of the patient. Administration can beaccomplished via single or divided doses.

In certain embodiments, in which an aqueous suspension is part of themanufacturing process, the aqueous suspension may contain the activematerial in admixture with excipients suitable for the manufacture ofaqueous suspensions. Such excipients are suspending agents dispersing orwetting agents such as a naturally occurring phosphatide, for examplelecithin, or condensation products of an alkylene oxide with fattyacids, for example polyoxyethylene stearate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such apolyoxyethylene with partial esters derived from fatty acids and hexitolanhydrides, for example polyoxyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives, for exampleethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such assucrose, mannitol, or trehalose.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives.

The term “pharmaceutical composition” means a composition comprising acompound as described herein and at least one component comprisingpharmaceutically acceptable carriers, diluents, adjuvants, excipients,or vehicles, such as preserving agents, fillers, disintegrating agents,wetting agents, emulsifying agents, suspending agents, sweeteningagents, flavoring agents, perfuming agents, antibacterial agents,antifungal agents, lubricating agents and dispensing agents, dependingon the nature of the mode of administration and dosage forms. The term“pharmaceutically acceptable carrier” is used to mean any carrier,diluent, adjuvant, excipient, or vehicle, as described herein. Examplesof suspending agents include ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,or mixtures of these substances. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monosterate andgelatin. Examples of suitable carriers, diluents, solvents, or vehiclesinclude water, ethanol, polyols, suitable mixtures thereof, vegetableoils (such as olive oil), and injectable organic esters such as ethyloleate. Examples of excipients include lactose, milk sugar, sodiumcitrate, calcium carbonate, and dicalcium phosphate. Examples ofdisintegrating agents include starch, alginic acids, and certain complexsilicates. Examples of lubricants include magnesium stearate, sodiumlauryl sulphate, talc, as well as high molecular weight polyethyleneglycols.

The term “pharmaceutically acceptable” means it is, within the scope ofsound medical judgment, suitable for use in contact with the cells ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, and are commensurate with a reasonablebenefit/risk ratio.

INCORPORATION BY REFERENCE

References and citations to other documents, such as patents, patentapplications, patent publications, journals, books, papers, webcontents, have been made throughout this disclosure. All such documentsare hereby incorporated herein by reference in their entirety for allpurposes.

EQUIVALENTS

Various modifications of the invention and many further embodimentsthereof, in addition to those shown and described herein, will becomeapparent to those skilled in the art from the full contents of thisdocument, including references to the scientific and patent literaturecited herein. The subject matter herein contains important information,exemplification and guidance that can be adapted to the practice of thisinvention in its various embodiments and equivalents thereof.

What is claimed is:
 1. An inhalable formulation comprising N-desmethylimatinib or a salt thereof, wherein the formulation does not includeimatinib.
 2. The inhalable formulation of claim 1, wherein theN-desmethyl imatinib is present in a therapeutically effective amount totreat a condition of the pulmonary cardiovascular system.
 3. Theinhalable formulation of claim 2, wherein the condition of the pulmonarycardiovascular system is pulmonary arterial hypertension (PAH).
 4. Theinhalable formulation of claim 1, wherein the inhalable formulation is adry powder.
 5. The inhalable formulation of claim 4, wherein the drypowder comprises micronized particles comprising a mass medianaerodynamic diameter in the range of 0.5-5 μm.
 6. The inhalableformulation of claim 1, wherein the salt is at least one selected fromthe group consisting of mesylate, glycollate, isethionate, xinafoate,furoate, trifenatate, HCl, sulfate, phosphate, lactate, maleate, malate,fumarate, tartrate, succinate, adipate, citrate, and malonate.
 7. Theinhalable formulation of claim 1, wherein the inhalable formulationfurther comprises one or more carrier agents.
 8. The inhalableformulation of claim 7, wherein the carrier agent is selected from thegroup consisting of lactose, magnesium stearate, leucine, isoleucine,dileucine, trileucine, lecithin, and distearylphosphatidylcholine(DSPC).
 9. A method of treating a condition of the pulmonarycardiovascular system, the method comprising providing to a subject aninhalable formulation comprising N-desmethyl imatinib or a salt thereof,wherein the formulation does not include imatinib.
 10. The method ofclaim 9, wherein the inhalable formulation is a dry powder.
 11. Themethod of claim 10, wherein the dry powder comprises micronizedparticles comprising a mass median aerodynamic diameter in the range of0.5-5 μm.
 12. The method of claim 9, wherein the subject is a human. 13.The method of claim 9, wherein the condition of the pulmonarycardiovascular system is pulmonary arterial hypertension (PAH).
 14. Themethod of claim 9, wherein the salt is at least one selected from thegroup consisting of glycollate, isethionate, xinafoate, furoate,trifenatate, HCl, sulfate, phosphate, lactate, maleate, malate,fumarate, tartrate, succinate, adipate, citrate, and malonate.
 15. Themethod of claim 9, wherein the inhalable formulation further comprisesone or more carrier agents.
 16. The method of claim 15, wherein thecarrier agent is selected from the group consisting of lactose,magnesium stearate, leucine, isoleucine, dileucine, trileucine,lecithin, and distearylphosphatidylcholine (DSPC).